Abstract
The 'ribosomal stress (RS)-p53 pathway' is triggered by any stressor or genetic alteration that disrupts ribosomal biogenesis, and mediated by several ribosomal proteins (RPs), such as RPL11 and RPL5, which inhibit MDM2 and activate p53. Inosine monophosphate (IMP) dehydrogenase 2 (IMPDH2) is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis and crucial for maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. It is highly expressed in many malignancies. We previously showed that inhibition of IMPDH2 leads to p53 activation by causing RS. Surprisingly, our current study reveals that Inauzhin (INZ), a novel non-genotoxic p53 activator by inhibiting SIRT1, can also inhibit cellular IMPDH2 activity, and reduce the levels of cellular GTP and GTP-binding nucleostemin that is essential for rRNA processing. Consequently, INZ induces RS and the RPL11/RPL5-MDM2 interaction, activating p53. These results support the new notion that INZ suppresses cancer cell growth by dually targeting SIRT1 and IMPDH2.
Highlights
With ∼22 million people living with cancers that are highly associated with alterations of multiple molecules and pathways, it is important to develop a multiple molecules-targeted therapy that can effectively kill cancer cells
IMPDH2 is the predominant isoform among its two isoenzymes, and often highly expressed in proliferating cells and neoplastic tissues (Ishitsuka et al, 2005; Gu et al, 2003), correlated to drug resistance, and has been used as a validated target for immunosuppressive, antiviral, and cancer-chemotherapeutic development [tiazofurin] (Malek et al, 2004; Gu et al, 2005; Chen and Pankiewicz, 2007; Borden and Culjkovic-Kraljacic, 2010)
By performing a biotin-INZ avidin affinity purification coupled with mass spectrometry (MS) analysis, we identified IMPDH2 as one of the top candidate proteins that INZ targets in cancer cells
Summary
With ∼22 million people living with cancers that are highly associated with alterations of multiple molecules and pathways, it is important to develop a multiple molecules-targeted therapy that can effectively kill cancer cells. Zhang et al demonstrated that Inauhzin's effect on the IMPDH enzyme triggered a response that did not involve the SIRT1 protein, and that led to a decrease in Mdm2 activity and restored p53 activity.
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